Project Summary Cancer is a systemic disease. Its growth and malignant progression relies not only on the intrinsic aberrant genetic and epigenetic makeup of tumor cells, but also on the tumor-induced systemic factors which impact cells in local and distant microenvironments. Importantly, there is dynamic crosstalk between the tumor- educated tissues and organs and the tumor itself, especially during metastatic progression. As the tumor reshapes its local microenvironment, coaxing it to support cancer growth, it exerts systemic effects, conquering the immune system and distant organs, leading not only to metastasis but also to vascular changes (vascular leakiness, coagulation), muscular and metabolic changes (cachexia), liver and lung failure, changes in bone density (osteoporosis or osteopetrosis), and neuropathies, but maybe above all, inflammation and immune suppression. The tumor exerts its systemic effects, coaxing the various organ systems of the host to support cancer growth through tumor-secreted factors, such as soluble factors (cytokines and chemokines) and exosomes (and exomeres, the novel particles we recently discovered) nanovesicles that carry complex cargo, including proteins, metabolites, DNA and coding as well as non-coding RNAs. The development of effective anti-metastatic therapies is predicated on our understanding of these iterative and complex interactions between the tumor and its host, and on devising ways to interrupt this communication. We developed novel approaches to analyze the heterogeneity and functional roles of tumor-derived exosomes and exomeres in metastasis as well as their capacity to induce systemic changes. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic cells could reverse immunosuppression, pre-metastatic niche formation and the systemic effects of cancer. In summary, we will focus on studying the mechanisms through which exosomes and exosomes regulate immune system mobilization, metabolic changes and plasticity of pre-metastatic and metastatic niches in cancer models and patients.